The absolute configuration of an inherently chiral phosphonatocavitand and its use toward the enantioselective recognition of L-adrenaline

Article abstract of DOI:10.1016/j.tetasy.2010.03.028

An inherently chiral ABii diphosphonato cavitand (±)-4 bearing a single quinoxaline bridging moiety was synthesized and resolved by chiral HPLC. Its chiroptical properties were investigated and VCD experiments allowed the determination of its absolute con

Full text of DOI:10.1016/j.tetasy.2010.03.028

Tetrahedron: Asymmetry 21 (2010± 1534–1541
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The absolute configuration of an inherently chiral phosphonatocavitand
and its use toward the enantioselective recognition of L-adrenaline
Jérôme Vachon , Steven Harthong , Béatrice Dubessy , Jean-Pierre Dutasta , Nicolas Vanthuyne b,
a
a
a
a,*
b
c
Christian Roussel , Jean-Valère Naubron
Laboratoire de Chimie, CNRS, École Normale Supérieure de Lyon, 46 Allée d’Italie, F-69364 Lyon, France
ISM2, Chirosciences, Université Paul Cézanne, Case A62, Avenue Escadrille Normandie Niemen, F-13397 Marseille, France
Spectropole, Université Aix-Marseille, Campus Scientifique de Saint Jérôme, Service 511, F-13397 Marseille, France
a
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
An inherently chiral ABii diphosphonato cavitand (± ±-4 bearing a single quinoxaline bridging moiety was
synthesized and resolved by chiral HPLC. Its chiroptical properties were investigated and VCD experi-
Received 8 March 2010
Accepted 26 March 2010
Available online 4 May 2010
ments allowed the determination of its absolute configuration. Distinguishable diastereomeric com-
-adrenaline were observed by 1H and P NMR together with a noticeable
31
plexes in solution with L
enantio-discrimination at 253 K (dr ꢀ2:1± in favor of the dextrorotatory cavitand (+±-4.
Ó 2010 Elsevier Ltd. All rights reserved.
Dedicated to Professor Henri Kagan on the
occasion of his 80th birthday
1
. Introduction
O
O
A
D
B
C
With the aim of mimicking biological functions in living sys-
O
O
O
O
tems, the design and the preparation of artificial molecular recep-
tors has generated a tremendous number of molecules with
different skeletons, sizes, and shapes. In this particular field, enan-
tioselective recognition using chiral host molecules has emerged,
leading also to various applications in asymmetric catalysis and
chiral separations. Calixarenes and resorcin[4]arenes are known
to be good candidates for the design of such chiral supramolecular
receptors, as illustrated by the increasing number of these deriva-
tives obtained in the last 15 years. However, in most compounds,
R
R
R
1
R
2
O
O
Figure 1. The resorcin[4]arene structure with its four possible bridging sites: A, B,
3
C, and D.
chirality is induced by the addition of stereogenic centers onto the
narrow or the wide rim of the calixarene, with the aromatic cavity
only being used as a rigid scaffold. In contrast to these chiral mol-
ecules, inherently chiral molecules have been also described. As
defined by Böhmer et al. in this case, ‘the chirality is not based on
a chiral group or subunit but in the absence of symmetry plane, an
the four available, giving compounds of type ABCD or AABC. The
only example in this category reported so far is the AABH cavitand
(
± ±-1 described by Cram et al., where H stands for the non-bridged
4
site (Fig. 2±. The second method is to have three identical sites and
the fourth one being unsymmetrical, leading to AAAB type chiral
molecules. Two examples have been reported by Soncini and Dal-
canale et al. (cavitand 2 in Fig. 2±, and Rebek Jr. et al. (cavitand 3,
Fig. 2±. Cavitand 2 was resolved using menthol as a chiral auxil-
3
a
inversion center or an alternating axis in the molecule as a whole’.
Several inherently chiral calix[n]arene (n = 4–8± have already been
reported, to the best of our knowledge, but only a few inherently
chiral resorcin[4]arene based cavitands have been described and
only one has been resolved. In these examples, the desymmetriza-
tion was caused by bridging the adjacent resorcinol moieties with
different groups (sites A, B, C, and D in Fig. 1± affording the cavitand
structure.
5
6
iary, to produce the first enantiopure inherently chiral cavitands
(
+±-2 and (ꢁ±-2. Complexation studies have been performed with
host (± ±-2, but only in the gas phase and with achiral guests. The
lack of strong binding groups and the rather achiral character of
the inner cavity precluded its use as an efficient enantioselective
Using this strategy, only two ways can lead to chiral com-
pounds. The first one is to have at least three different sites of
7
receptor in solution.
The versatility of the cavitands based on the phosphorylated
8
resorcin[4]arenes such as the tetraphosphonatocavitands, which
9
show remarkable binding properties toward alcohols, metal
*
Corresponding author. Tel.: +33 472 728 382; fax: +33 472 728 860.
1
0
11
E-mail address: jean-pierre.dutasta@ens-lyon.fr (J.-P. Dutasta±.
ions, and ammonium cations, are good candidates for the
0
957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.028

J. Vachon et al. / Tetrahedron: Asymmetry 21 (2010) 1534–1541
1535
R'
N
N
O
O
O
O
O
N
N
N
O
O
O
O
O
O
O
R
R
R
R
R
R
R
R
OH
N
N
OH
O
O
N
N
N
1
: R = C H
2: R = C H ; R'=CH OH
5
11
6
13
2
R''
R'
HN
O
O
NH
H
N
N
R'
O
O
O
N
O
O
O
O
O
R
R
R
R
O
O
O
R'
N
HN
H
R'
HN
O
HN
O
R'
R'
3
: R = C11H23 ; R' = C H15; R'' = adamantyl
7
Figure 2. Examples of inherently chiral cavitands of type AABH 1 and AAAB 2 and 3.
design of inherently chiral cavitands. For instance, the new host
± ±-4 was obtained by adding a quinoxaline bridge to an ABii type
It is important to note that in the tetraphosphonatocavitand
hosts the phosphorus bridges are often prochiral and as a result,
the phosphorus become chiral when the symmetry of the molecule
is broken, especially in partially bridged phosphonatocavitands.
This introduces new stereogenic centers depending on the inward
or outward orientation of the phosphorus substituents (vide infra±.
Herein, the configuration at the phosphorus atom is important, but
does not interfere with the inherent chirality of the host, which is
closely related to the three-dimensional arrangement of the molec-
ular cavity and its curvature. In this study, the cR or cS nomencla-
ture used to define the configuration of the inherently chiral
(
phosphonatocavitand (Fig. 3±. As stated above, AB (AC± defines the
proximal (distal± positions of the two phosphorus groups, while ii
corresponds to the inward orientations of the two P@O groups.
Thus, the ABii structure possesses; (i± two P@O bonds oriented to-
ward the cavity (complexation sites for ammonium guests±; (ii± a
quinoxaline bridge that can favor p-interactions with guests bear-
ing aromatic groups; (iii± free phenol OH groups for H-bonding;
and (iv± an aromatic cavity for guest encapsulation through CH–
p
or cation–p interactions.
N
N
HO
O
O
OH
N
N
HO
O
O
O
O
OH
O
R
R
R
R
R
R
R
R
cR
cS
O
O
O
O
O
P
P
P
P
O
O
O
O
cR-4
cS-4
Figure 3. The two enantiomers of cavitand (± ±-4 (R = C11H23± of ABii type bearing two phosphonate bridging groups and one quinoxaline bridge (wide rim up±.

1
536
J. Vachon et al. / Tetrahedron: Asymmetry 21 (2010) 1534–1541
cavitands refers to that one proposed for the calixarene structures,
which considers the curvature of the cavity and the usual sequence
rules for the bridging moieties.12
vase-kite exchange was still observed as a result of the developing
Coulombic repulsion in the vase geometry. As such behavior could
occur with compounds 4 and 10, VT-NMR experiments in CD
2 2
Cl
Herein, we report on the synthesis and the resolution of the chi-
ral diphosphonatocavitand (± ±-4. Its absolute configuration was
determined by VCD and correlated to CD measurements. The com-
plexation properties of 4 toward an ammonium guest of biological
and CDCl , and pH titration studies in CDCl , were performed for
3
3
these two mixed-bridged cavitands. In both cases, no significant
1
H NMR chemical shift of the methine proton facing the quinoxa-
line bridge was observed, either by lowering the temperature
(down to 213 K±, or after the addition of trifluoroacetic acid (up
to 10 equiv±. As a consequence, for these mixed-bridged cavitands
the vase-kite interconversion is absent and, according to the NMR
data, the vase form predominates (Fig. 4±.
relevance, namely L-adrenaline have been investigated.
2
2
. Results and discussion
.1. Synthesis
2
.3. Chiroptical properties
The acid-catalyzed co-condensation between resorcinol and
dodecanal, led predominantly to resorcin[4]arene 5 (Scheme 1±.
The resolution of (± ±-4 was performed by semi-preparative
HPLC using a Chiralpak IC column eluted with hexane/ethanol/
1
3
14
The partially bridged compounds, with inward orientation of the
P@O groups, were obtained by following the two-step synthesis
previously described for the synthesis of triphosphonatocavit-
CHCl
3
80/10/10 mixture. This method afforded enantiopure (ꢁ±-4
25
D
{
t
R
= 4.8 min; ½
a
ꢂ
¼ ꢁ34 (c 0.59, CHCl
3 R
±} and (+±-4 {t = 10.5 min;
25
D
½
a
ꢂ
¼ þ34 (c 0.59, CHCl
3
±} with a productivity of 2 mg of pure
1
5
ands. Compound 5 was treated with two equivalents of dichloro-
phenylphosphine in the presence of pyridine followed by the
in situ addition of sulfur.16 This gave rise to three major com-
pounds: the trithiophosphonate iiiPS derivative 6 (19%± and the
two dithiophosphonate cavitands ACiiPS 7 (8%± and ABiiPS 8
enantiomer (ee >99%± per hour. The CD spectra of a CH
2
Cl
2
solution
ꢁ5
of (+±-4 (c ꢀ4 ꢃ 10 M± displayed bisignated curves with a posi-
tive Cotton effect around 235 nm and two consecutive negative
25
Cotton effects at 245 and 290 nm (Fig. 5±. As expected, a solution
of (ꢁ±-4 in CH
2 2
Cl showed an identical and inverted signal, con-
firming the enantiomeric relationship between (+±-4 and (ꢁ±-4.
(
24%±, which were separated by column chromatography. If this
17
method has already been reported, the isolation of compounds
of type ABiiPS is unprecedented.
2
.4. Determination of the absolute configuration by VCD
Contrary to the compounds of type iii or ACii, the ABii structure
can be desymmetrized by adding a third and different bridge onto
the crown of the cavitand. Prior to introducing dissymmetry to this
compound, ABiiPS 8 was first transformed into ABiiPO 9 using a
slight excess of m-CPBA (3 equiv± as an oxidant; the reaction oc-
curred with retention of configuration, and the P@O groups
adopted the inward orientation.18 In the P NMR spectra, the sig-
nal at 78 ppm which is characteristic of the thiophosphorylated
species disappears to give a single peak around 8 ppm, which is
characteristic of the phosphorylated species.19 The phosphonatoc-
avitand 9 was isolated in 89% yield after chromatography. The
quinoxaline bridges have been already used for the preparation
of deep cavity cavitands.20 In the present case, the addition of
Recently, vibrational circular dichroism (VCD± spectroscopy has
become a valuable complementary or alternative method for pre-
26
dicting the absolute configuration of non-racemic compounds.
Although a rather large variety of structurally different chemical
substances have been analyzed, to the best of our knowledge, no
experimental and theoretical investigations on inherently chiral
calixarene type molecules have been reported. The absolute config-
uration of the enantiomers of cavitand 4 was assigned from the
comparison between experimental and calculated VCD spectra.
Due to the size of the molecule, two approximations were consid-
ered for the calculations of the IR and VCD spectra, performed at
the DFT level using B3PW91 functional and 6-311G(d± basis set:
31
1
equiv of 2,3-dichloroquinoxaline leads mainly to compound
± ±-4 bearing one quinoxaline bridge, and to the bis-quinoxaline
derivative 10, which were isolated by column chromatography.
(
i± the C11
H23 groups at the narrow rim were substituted succes-
(
sively by CH
3
and CH CH groups (m4-CH and m4-CH CH ,
2
3
3
2
3
respectively, in Fig. 6±; (ii± only two vase conformations (I and II±
for each simplified cavitand have been used for the calculations
of IR (Fig. 7± and VCD (Fig. 8± spectra. These two vase conforma-
tions only differ by the relative orientation of the hydroxyl groups.
For both models, the energy for conformation (I± is about
2
.2. Vase-kite conformations
Cavitands bearing four quinoxaline bridges are known to exist
ꢁ1
as two conformational isomers described as vase and kite forms.
Interconversion between these two forms can be triggered either
with temperature or pH variations.21 The vase-kite switching is
strongly solvent-dependent and was observed only in apolar and
1.5 kJ mol lower than that for conformation (II±.
Despite these two approximations, the agreement between
experimental and calculated IR and VCD spectra is quite good. The
calculated spectra were very similar using m4-CH (I± or m4-
3
2
2
non-aromatic solvents such as CDCl
/CS
3 2
2
, CD Cl
2
, and C
2
D
2
Cl
4
.
CH CH (I± on the one hand, and m4-CH (II± or m4-CH CH (II± on
2
3
3
2
3
1
The conformational equilibrium was followed by H NMR by the
monitoring of the chemical shift of the methine protons situated
near the quinoxaline moieties. A low field resonance corresponds
to the vase form whereas a high field shift corresponds to the kite
form. It has been proven that in apolar and non-aromatic solvents,
the vase form of cavitands bearing four quinoxaline bridges was
predominant above room temperature while the kite form was
predominant at low temperatures (<223 K±.23 If this behavior has
been well studied for cavitands bearing four quinoxaline bridges,
very little data are available for the mixed-bridged cavitands.
Diederich et al. showed that the absence of one quinoxaline bridge
the other hand (Figs. 7 and 8±. Particularly, the intensities, the signs
and the shapes of the bands 1–7 are well reproduced mainly in the
calculated spectra of the conformations m4-CH (I± or m4-CH CH (I±,
3
2
3
whereas a better agreement is obtained for the bands 8–11 with the
conformation m4-CH (II± or m4-CH CH (II±. The vibrational modes
3
2
3
that are associated to these bands concern essentially the core of
the cavitand and do not seem to be strongly affected by the four R
chains. Thus, we can reasonablyuse these bands in order to safely as-
sign the absolute configuration cR to (ꢁ±-4.
2.5. Recognition of L-adrenaline guest
2 2
switches off the VT-triggered conformational exchange in CD Cl ,
with the cavitand being fixed in the vase conformation over the
Taking advantage of the functionalities, the size and the geom-
etry of cavitand (± ±-4, we examined its recognition properties to-
entire temperature range from 203 to 313 K.24 The pH-triggered

J. Vachon et al. / Tetrahedron: Asymmetry 21 (2010) 1534–1541
1537
HO
OH
HO
HO
OH
OH
1
) C H PCl
6 5 2
R
R
R
HO
OH
CH -(CH ) -CHO
2) S8
3
2 10
HCl/EtOH
1%
Toluene/pyridine
R
7
HO
OH
5
O
OH
O
P
HO
P
P
S
S
O
O
OH
O
O
HO
O
R
R
R
R
R
R
R
R
OH
S
S
S
P
P
O
O
O
OH
3
iPS
ACiiPS
6
19%
7
8%
O
OH
O
OH
P
P
P
S
O
O
OH
OH
O
O
OH
OH
R
R
R
R
R
R
R
m-CPBA
CHCl3
R
O
85%
S
O
P
OH
O
OH
O
ABiiPO
ABiiPS
8
24%
9
2
,3-dichloroquinoxaline
N
Cs CO /DMF
2
3
N
N
HO
O
O
N
O
N
N
HO
O
O
O
O
O
R
R
R
R
R
R
R
R
O
O
O
O
O
O
P
P
P
P
O
O
O
O
(
±)-4
9%
10
29%
3
Scheme 1. Synthesis of cavitand (± ±-4 (R = C11H23±.
ward selected enantiopure ammonium guests of biological rele-
vance bearing aromatic moieties. We turned our attention to
system. Only few examples of adrenergic synthetic hosts have been
2
7
described.
Upon the addition of a solution of 1 equiv of (± ±-4 in CDCl
-adrenaline picrate salt [ -11][pic] (insoluble in CDCl ±, the com-
plete solubilization of the guest was obtained and a highfield
L-adrenaline
L
-11, which matches such criteria. This compound is
3
to
known to take part in complex biological processes such as signal-
ing pathways, storing, and retrieving information in the neuronal
L
L
3

1
538
J. Vachon et al. / Tetrahedron: Asymmetry 21 (2010) 1534–1541
Figure 4. Model structures of the vase (a± and kite (b± conformations of the
quinoxaline-bridged ABii cavitand 4 (long alkyl chains have been replaced by CH
3
groups±.
Figure 7. Comparison of the experimental IR spectrum of (± ±-4 with predicted IR
spectra of the stable conformation of m4-CH CH (I± (a±, m4-CH CH (II± (b±, m4-
CH (I± (c± and m4-CH (II± (d±, at the B3PW91/6-311G(d± level. For predicted spectra,
2
3
2
3
3
3
wave numbers are scaled by the factor 0.9676.
(c ꢀ4 ꢃ 10ꢁ M±.
5
Figure 5. CD spectra of (+±-4 (blue± and (ꢁ±-4 (red± in CH
2
Cl
2
Figure 8. Comparison of experimental VCD spectra of (+±-4 and (ꢁ±-4 with
2 3
predicted VCD spectra of the stable conformation of m4-CH CH (I± (a±, m4-
2 3 3 3
CH CH (II± (b±, m4-CH (I± (c± and m4-CH (II± (d±, at the B3PW91/6-311G(d± level.
For predicted spectra, wave numbers are scaled by the factor 0.9676.
the host–guest exchange becomes slow on the 1H NMR timescale
and the methyl resonance of the guest split into two signals corre-
sponding to the two diastereomers, namely [(+±-4][
(ꢁ±-4][ -11][pic] (Fig. 9c±. The same occurs in the
spectrum as two sets of doublets, which overlap as a triplet-like
L-11][pic] and
31
[
L
P NMR
ꢁ
1
signal, were obtained. The association constants K(+± ꢀ435 M
ꢁ1
and
K
(ꢁ± ꢀ140 M
-11][pic], respectively, were determined by H NMR at
53 K. This gives a rough estimation of the K(+±/K(ꢁ± ratio of 3:1,
-adrenaline. In the
presence of a 1:0.4 host–guest ratio, a 2:1 diastereomeric ratio
for the complexes [(+±-4][L-11][pic] and
1
[
2
(ꢁ±-4][
L
indicating that (+±-4 better accommodates
L
1
31
was observed on the H and P NMR spectra at 253 K in favor of
[(+±-4][
Figure 6. Optimized vase conformations of the simplified models of compound 4:
m4-CH
3
(I±, m4-CH
3 2
(II±, m4-CH CH
3 2
(I± and m4-CH CH
3
(II± at the B3PW91/6-311G(d±
L
-11][pic] (Fig. 9d±. The use of enantiopure (+±-4 and (ꢁ±-4
level.
allowed us to assign each diastereomeric pair (Fig. 9e and f±. Under
similar conditions, more free cavitand is observed in the 31P NMR
spectrum when using (ꢁ±-4 (Fig. 9f± compared to (+±-4 (Fig. 9e±.
chemical shift of the NCH
3
protons was noticed in the 1H NMR
3
As [L-11][pic] is insoluble in CDCl , cavitand 4, which plays the role
spectrum (d = ꢁ1.3 ppm± indicating the complexation of this guest
into the cavity of (± ±-4 (Fig. 9b±. The two expected diastereomeric
complexes were not observed by NMR at room temperature due to
the fast host–guest exchange rate on the NMR timescale. At 253 K
of a solid–liquid extractant, in its dextrorotatory form better
extracts this guest to the liquid phase compared to the laevorotatory
enantiomer. This clearly indicates the preference of L-adrenaline
guest toward the (+±-4 enantiomer.

J. Vachon et al. / Tetrahedron: Asymmetry 21 (2010) 1534–1541
1539
Figure 9. 1H and 31P NMR spectra (CDCl
L
-11][pic] 1:1 (293 K±; (c± (± ±-4/[
L-11][pic] 1:1 (253 K±; (d± (± ±-4/[
L-11][pic] 1:0.4 (253 K±; (e± (+±-4/
3
± of (a± (± ±-4 (293 K±; (b± (± ±-4/[
[L
-11][pic] 1:1 (253 K±; (f± (ꢁ±-4/[
L-11][pic] 1:1 (253 K±; (g± (± ±-4 (253 K±.
3
. Conclusion
instrument, detecting positive (+± ions in the ESI mode. Electronic
Circular Dichroism (ECD± spectra were recorded on a JASCO J-815
CD spectrometer in a 1.0 cm quartz cell; k are given in nanometer
In conclusion, we have demonstrated that the new chiral ABii
2
ꢁ1
phosphonatocavitand (± ±-4, obtained by desymmetrization of the
cavity, has been successfully resolved by semi-preparative chiral
HPLC. The calculations of the IR and VCD spectra performed at
the DFT level (B3PW91 functional± and the comparison with the
experimental data allows us to predict the absolute configuration
of each enantiomer. Compound (± ±-4 was then used as a discrimi-
and molar circular dichroic absorptions De in cm mmol .
4.2. Enantioseparation
Resolution of enantiomers was performed using a Lachrom Elite
HPLC driven by an EZChrom software, with a L-2130 pump, a L-
2200 sampler, a L-2350 oven, a L-2455 diode array detector, and
a Jasco CD-2455 circular dichroism detector. The separation was
nating host toward
ence toward -adrenaline, with regard to the laevorotatory
L-adrenaline. Cavitand (+±-4 showed a prefer-
L
enantiomer. Ongoing efforts are made to better understand the
non-covalent interactions between receptors and neurotransmit-
ters. Other types of guest molecules are being investigated to
broaden the field of application of this new chiral phosphonatoca-
vitand, as well as the development of other chiral and enantiopure
host molecules.
obtained with successive additions (500
on a semi-preparative chiral column Chiralpak IC (250 ꢃ 10 mm,
m± thermostated at 30 °C with UV detector at 254 nm and CD
detector at 277 nm. Enantiomeric excesses (ees± were determined
by HPLC using commercial analytical chiral column Chiralpak IC
lL each, every 15 min±
5
l
(250 ꢃ 4.6 mm, 5
lm± using same conditions. Optical rotations
2
5
were reported as follows: ½
aꢂ
(c g/100 mL, in solvent± and were
D
performed on a Perkin–Elmer 241 MC, equipped with a sodium
4
4
. Experimental
lamp (589 nm± and a 10 cm double envelop cell thermostated at
2
5 °C.
.1. General
Reactions were carried out using commercial available reagents
4.2.1. Cavitand (ꢁ)-4
in oven-dried apparatus. Toluene, Et
distilled from sodium benzophenone under nitrogen just before
use. CH Cl was dried over powdered CaH and distilled under
nitrogen just before use. NMR experiments were recorded on
00 MHz (4.7 T± or 500 MHz (11.7 T± NMR spectrometers. J Cou-
pling constants are in hertz; chemical shifts are in d values relative
2
O, and THF were dried and
The resolution was performed on the semi-preparative HPLC
starting from 40 mg of (± ±-4; 18 mg of (ꢁ±-4 were recovered by col-
2
2
2
lecting the fractions eluted between 3.5 and 6 min: t = 4.8 min
R
2
5
(hexane/ethanol/chloroform 8/1/1, 1 ml/min±; ½
a
ꢂ
¼ ꢁ34 (c 0.59,
D
2
CHCl ±.
3
1
13
31
13
31
to Me
4
Si ( H and C± or H
3
PO
4
85% ( P±. C and P NMR spectra
4.2.2. Cavitand (+)-4
are proton decoupled. Spectra are reported as follows: chemical
shift (d ppm±, multiplicity (s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet±, coupling constants (Hz±, integration
and assignment. HRMS was recorded on a commercial apparatus
The resolution was performed on the semi-preparative HPLC
starting from 40 mg of (± ±-4; 18 mg of (+±-4 were recovered by col-
lecting the fractions eluted between 8 and 13 min: t = 10.5 min
R
2
5
(hexane/ethanol/chloroform 8/1/1, 1 ml/min±; ½
a
ꢂ
¼ þ34 (c 0.59,
D
(
ESI Source, TOF±. Mass spectra were acquired on an ion trap
CHCl ±.
3

1
540
J. Vachon et al. / Tetrahedron: Asymmetry 21 (2010) 1534–1541
4
.3. IR and VCD measurements
4.5.2. Cavitand 7
LSIMS m/z 1403.7633 [M+Na]+ (calcd 1403.7633±. 31P NMR
1
Infrared (IR± and vibrational circular dichroism (VCD± spectra
(CDCl
200.13 MHz± d 0.87 (m, 12H, –CH
–CH –(CH –CH ±, 2.12 (m, 4H, (–CH
4H, (–CH –(CH
J = 7.20 Hz±, 6.50 (s, 4H±, 7.18 (s, 4H±, 7.54 (m, 6H±, 8.17
3
, 300 K, 80.02 MHz± : d 77.32 (2P±. H NMR (CDCl
–(CH –CH ±, 1.25 (m, 72H,
–(CH –CH ±, 2.30 (m,
±, 4.28 (t, 2H, J = 7.20 Hz±, 4.70 (t, 2H,
3
, 300 K,
were recorded on a Bruker PMA 50 accessory coupled to a Vertex70
Fourier transform infrared spectrometer. A photoelastic modulator
2
2
±
9
3
2
2
±
9
3
2
3
2
±
9
3 b
±
(
Hinds PEM 90± set at l/4 retardation was used to modulate the
2
2 9 3 a
± –CH ±
3
handedness of the circular polarized light at 50 kHz. Demodulation
was performed by a lock-in amplifier (SR830 DSP±. An optical low-
pass filter (<1800 cm ± before the photoelastic modulator was
used to enhance the signal/noise ratio. transmission cell
equipped with CaF windows and a 210 m spacer was used. All
solutions were prepared from 7.4 mg sample in 220 L CD Cl
The VCD spectra of each pure enantiomer were measured and sub-
tracted with each other in order to eliminate artifacts. For the indi-
vidual spectra of the enantiomers, about 12,000 scans were
averaged at 4 cm resolution (corresponding to 3 h measurement
time±. For the infrared spectrum the cell filled with CD Cl served
3
3
13
(dd, 4H,
50.32 MHz± d 14.11 (–CH
CH –CH ±, 27.93 (–CH –(CH
(CH –CH –CH –CH ±, 29.41
(–CH –(CH –CH ±, 31.49 (–CH
CH –(CH –CH ±, 33.71, 34.04 (CH
J
H–H = 7.47 Hz,
J
P–H = 14.62 Hz±. C NMR (CDCl
–(CH –CH ±, 22.69 (–CH –(CH
–CH –CH –CH ±, 28.06 (–CH
(–CH –(CH –CH ±,
–CH –(CH –CH ±, 31.94 (–CH
–CH –(CH –CH ±, 35.44,
3
, 300 K,
ꢁ1
2
2
±
9
3
2
2
±
8
–
–
A
2
3
2
2
±
7
2
2
3
2
2
l
2
±
7
2
2
3
2
2
±
9
3
29.70
l
2
2
.
2
2
±
9
3
2
2
2
±
8
3
2
–
2
2
±
8
3
2
2
2
±
8
3
3
112.61, 122.90, 128.50 (d, J = 15.7 Hz±, 129.07, 130.77, 130.99 (d,
2
2
1
J = 11.7 Hz±, 131.66 (d, J = 164.8 Hz±, 133.30, 145.12 (d,
J = 10.9 Hz±, 151.29.
ꢁ1
2
2
as a reference. The spectra are presented without smoothing and
further data processing.
4.5.3. Cavitand 8
LSIMS m/z 1381.7834 [M+H] (calcd 1381.7822±. 31P NMR (CDCl
+
3
,
1
3
00 K, 80.02 MHz±: d 80.69 (2P±. H NMR (CDCl
3
, 300 K, 200.13 MHz±
4
.4. DFT calculations
d 0.85 (m, 12H, –CH
.12 (m, 4H, (–CH
CH ± ±, 4.24 (t, 2H, J = 6.84 Hz±, 4.67 (t, 2H, J = 6.84 Hz±, 5.54 (s,
3 a
1H±, 6.54 (s, 2H±, 6.67 (s, 1H±, 7.03 (s, 1H±, 7.25 (s, 2H±, 7.32 (s, 1H±,
2
–(CH
–(CH
2
±
9
–CH
–CH
3
±, 1.25 (m, 72H, –CH
2
–(CH
2
±
9
–CH
3
±,
–
2
2
2
±
9
3
±
b
±, 2.31 (m, 4H, (–CH
2
–(CH ±
2
9
3
3
The geometry optimizations, vibrational frequencies, IR absorp-
tion, and VCD intensities were calculated with Density Functional
Theory (DFT± using B3PW91 functional and a 6-311G(d± basis set.
Frequencies were scaled by a factor of 0.9676. The IR absorption
and VCD spectra were constructed from calculated dipole and rota-
tional strengths assuming Lorentzian band shape with a half-width
3
3
7.56 (m, 6H±, 8.15 (dd, 4H,
J
H–H = 7.47 Hz,
C NMR (CDCl , 300 K, 50.32 MHz± d
±, 22.69 (–CH –(CH –CH –CH ±, 28.06
–CH ±, 29.41 (–CH –(CH –CH
31.10 (–CH –CH –(CH –CH ±,
±, 33.41 (–CH –CH –(CH –CH
JP–H = 14.94 Hz±, 8.53
1
3
(s, 2H±, 8.72 (s, 2H±.
14.11 (–CH –(CH –CH
3
2
2
±
9
3
2
2
±
7
2
3
(–CH
(–CH
(–CH
2
2
2
–(CH
–(CH
–CH
2
±
7
–CH
–CH
2
3
8
–CH
±,
–CH
2
3
2
2
±
9
3
±, 29.74
3
31.94
ꢁ1
at half maximum of 6 cm . All calculations were performed using
GAUSSIAN03.
2
±
9
2
2
2
±
8
2
8
2
–(CH
2
±
3
2
2
2
±
8
3
±, 33.60,
3
5.83, 102.96, 112.23, 119.95, 122.05, 123.56, 123.96, 128.40 (d,
3
2
4
.5. Synthesis of cavitands 6–8
J = 15.7 Hz±, 129.16, 130.34, 131.04 (d, J = 11.8 Hz±, 131.48 (d,
J = 171.5 Hz±, 132.89, 136.18, 146.11, 150.16, 152.56.
1
The azeotropic distillation, by means of a Dean and Stark appa-
ratus, of a suspension of 5 (2.12 g, 1.92 mmol± in toluene (190 mL±
was performed overnight under dry argon to remove traces of
water from the starting material. Afterwards, pyridine (1 mL,
4.6. Synthesis of cavitand 9
m-Chloroperoxybenzoic acid (140 mg, 0.8 mmol± was added to a
1
2.4 mmol± and dichlorophenylphosphine (0.52 mL, 3.83 mmol±
3
solution of cavitand 8 (377 mg, 0.26 mmol± in CHCl (38 mL±. The
were added dropwise at 0 °C. The resultant mixture was stirred
at 0 °C for 45 min and then allowed to reach room temperature.
Sulfur (0.184 g, 5.75 mmol± was then added and the solution was
heated at reflux temperature for 6 h. The resulting mixture was fil-
tered at room temperature and the filtrate was concentrated under
vacuum to give a beige residue (3.40 g±. Silica gel column chroma-
mixture was stirred at room temperature for 1 h. After evaporation
of the solvent, the crude compound was recrystallized fromMeOH to
give 9 as a white solid (300 mg, 85%±. LSIMS m/z 1421.85
+
31
[M+THF+H] (calcd 1421.88±. P NMR (CDCl
3
, 300 K, 202.45 MHz±
, 300 K, 500.10 MHz± d 0.85 (m, 12H,
±, 1.25 (m, 72H, –CH –(CH –CH ±, 2.12 (m, 4H,
±, 2.27 (m, 4H, (–CH –(CH –CH ±, 4.29 (t,
1
: d 8.30 (2P±. H NMR (CDCl
–CH –(CH –CH
(–CH –(CH –CH
3
2
2
±
9
3
2
2
±
9
3
tography (eluent CH
2
Cl
2
/ethyl acetate: from 98:2 to 90:10± of the
2
2
±
9
3
±
b
2
2
±
9
3 a
±
3
3
residue afforded the iii compound 6 (0.555 mg, 0.37 mmol, 19%±
2H, J = 7.62 Hz±, 4.60 (t, 2 H, J = 7.62 Hz±, 6.10 (s, 1H±, 6.59 (s,
1
5
as a white solid. Further elution with CH
9
0
2
Cl
0:10 to 80:20 afforded the ACii compound
.16 mmol, 8%± as a white solid. Further elution with CH
2
/ethyl acetate: from
(0.222 mg,
Cl /ethyl
2H±, 6.86 (s, 1H±, 6.89 (s, 1H±, 7.11 (s, 2H±, 7.30 (s, 1H±, 7.56 (m,
3
3
P–H
4H±, 7.65 (t, 2H, J = 7.31 Hz±, 8.04 (dd, 4H, J J =
H–H = 7.43 Hz, 3
7
1
3
2
2
14.19 Hz±, 8.65 (s, 2H±, 10.11 (s, 2H±. C NMR (CDCl
50.32 MHz± d 14.26 (–CH –(CH –CH ±, 23.09 (–CH –(CH
–CH –CH ±, 29.79 (–CH
±, 31.23 (–CH –CH –(CH
3
, 300 K,
acetate: from 80:20 to 70:30 afforded the ABii compound 8
0.679 mg, 0.46 mmol, 24%± as a white solid.
2
2
±
9
3
2
2
±
7
–CH
–(CH
–CH
2
–
9
–
3
±,
(
CH
CH
3
±, 28.45 (–CH
±, 30.13 (–CH
2
–(CH
–(CH
2
±
7
–CH
–CH
2
2
3
2
2
±
3
2
2
±
9
3
2
2
2
±
8
4
.5.1. Cavitand 615
2 2 2 8 3
32.35 (–CH –CH –(CH ± –CH ±, 33.94, 36.40, 103.30, 111.52,
118.23, 122.96, 123.80, 124.43, 125.23, 127.91, 130.01, 132.27,
132.60, 134.87, 137.30, 146.11, 146.70, 151.81, 156.09.
LSIMS m/z 1541.7339 [M+Na] (calcd 1541.7334±. 31P NMR
+
1
(
81.02 MHz, 300 K, CDCl
3
±: d 78.17 (2P±; 79.15 (1P±. H NMR (CDCl
3
,
3
–
00 K, 200.13 MHz± d 0.91 (m, 12H, –CH
2
–(CH
2
±
9
–CH
3
±, 1.30 (m, 72,
±, 4.44 (t, 1H,
CH –(CH –CH ±, 2.35 (m, 8H, –CH –(CH
2
2
±
9
3
2
2
±
9
–CH
3
4.7. Synthesis of cavitands 10 and (±)-4
J = 8,0 Hz±, 4.75 (m, 3H±, 6.54 (s, 2H±, 6.72 (s, 2H±, 7.23 (s, 2H±, 7.37
(
s, 2H±, 7.53 (m, 9H±, 8.22 (m, 6H±. 13C NMR (CDCl
3
, 300 K,
Cesium carbonate (77 mg, 0.24 mmol± and 2,3-dichloro-quinox-
aline (16 mg, 0.08 mmol± were added to a solution of cavitand 9
(100 mg, 0.075 mmol± in DMF (5 mL±. The mixture was stirred at
room temperature for 48 h and then poured into ethyl acetate
(30 mL±. The solution was extracted with water (10 ꢃ 5 mL±, dried
5
0.32 MHz± d 14.10 (CH
CH ±, 28.05 (CH –(CH –CH
9.72 (CH –(CH –CH ±, 30.96 (CH
CH –CH –(CH –CH ±, 33.85 (CH –CH
2
–(CH
2
±
9
–CH
3
±, 22.68 (CH
±, 29.39 (CH
–CH –(CH
–(CH
2
–(CH
–(CH
–CH
–CH ±, 35.74,
2
±
8 2
–CH –
3
2
2
±
8
2
–CH
2
–CH
3
2
2
±
9
–CH
3
±,
2
(
2
2
±
9
3
2
2
2
±
8
3
±, 31.94
2
2
2
±
8
3
2
2
2
±
8
3
3
3
1
1
5.97, 111.95, 119.46, 121.72, 122.93, 128.26 (d, J = 15.6 Hz±,
2 4
over Na SO , and evaporated to dryness under vacuum to give a
28.37 (d, J = 15.6 Hz±, 129.83, 130.00, 131.03 (d, 2J = 11.8 Hz±,
3
brown residue. The crude compound was purified by silica gel col-
umn chromatography (eluent CH Cl /THF from 99:1 to 9:1± to give
1
31.84 (d, J = 168.4 Hz±, 132.73, 135.05, 135.96, 146.24, 151.57.
2
2

J. Vachon et al. / Tetrahedron: Asymmetry 21 (2010) 1534–1541
1541
compound 10 as a white solid (35 mg, 29%±. Further elution with
CH Cl /THF from 9:1 to 7:3 gave compound (± ±-4 as a white solid
42 mg, 39%±.
2. (a± Moberg, C. Angew. Chem., Int. Ed. 2006, 45, 4721; (b± Fernandes, S. A.;
Nachtigal, F. F.; Lazzarotto, M.; Fujiwara, F. Y.; Marsaioli, A. J. Magn. Reson.
Chem. 2005, 43, 398; (c± Yakovenko, A. V.; Boyko, V. I.; Kalchenko, V. I.; Baldini,
L.; Casnati, A.; Sansone, F.; Ungaro, R. J. Org. Chem. 2007, 72, 3223.
2
2
(
3
.
(a± Visotsky, C. S. M.; Böhmer, V. Adv. Supramol. Chem. 2000, 7, 139; (b±
Cherenok, S.; Dutasta, J.-P.; Kalchenko, V. Curr. Org. Chem. 2006, 10, 2307; (c±
Simulescu, V.; Ilia, G. J. Inclusion Phenom. Macrocycl. Chem. 2010, 66, 3.
Cram, D. J.; Tunstad, L. M.; Knobler, C. B. J. Org. Chem. 1992, 57, 528.
4
.7.1. Cavitand 10
LSIMS m/z 1601.8706 [M+H] (calcd 1601.8709±. 31P NMR
CDCl , 300 K,
, 300 K, 202.45 MHz± : d 8.14 (2P±. 1H NMR (CDCl
00.10 MHz± d 0.86 (m, 12H, –CH –(CH –CH ±, 1.26 (m, 64H,
CH –CH –(CH –CH ±, 1.44 (m, 8H, –CH –CH –(CH –CH ±, 2.30
–(CH –CH
±, 4.67 (t, 1H, 3J = 7.40 Hz±, 5.78 (t, 1H,
J = 8.17 Hz±, 6.81 (s, 1H±, 7.19 (s, 1H±, 7.21 (s, 1H±, 7.45 (s, 2H±,
+
4
.
(
5
–
3
3
5. Soncini, P.; Bonsignore, S.; Dalcanale, E.; Ugozzoli, F. J. Org. Chem. 1992, 57,
608.
Renslo, A. R.; Tucci, F. C.; Rudkevich, D. M.; Rebek, J., Jr. J. Am. Chem. Soc. 2000,
22, 4573; Renslo, A. R.; Rudkevich, D. M.; Rebek, J., Jr. J. Am. Chem. Soc. 1999,
121, 7459.
4
2
2
±
9
3
6.
2
2
2
±
8
3
2
2
2
±
8
3
1
(
m, 8H, –CH
2
2
±
9
3
3
7. Vincenti, M.; Dalcanale, E.; Soncini, P.; Guglielmetti, G. J. Am. Chem. Soc. 1990,
112, 445.
8. Dutasta, J.-P. Top. Curr. Chem. 2004, 232, 55.
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Kalenius, E.; Vainiotalo, P.; Mulatier, J.-C.; Dutasta, J.-P.; Dalcanale, E. Chem. Eur.
J. 2008, 14, 5772.
3
7
7
1
.45 (s, 1H±, 7.45 (m, 6H±, 7.50 (m, 4H±, 7.83 (d, 2H, J = 8.05 Hz±,
.97 (m, 6H±, 8.46 (s, 1H±. 13C NMR (CDCl
, 300 K , 50.32 MHz± d
4.14 (–CH –(CH –CH ±, 22.72 (–CH –(CH
–CH ±, 28.09 (–CH –(CH –CH ±, 29.45 (–CH
9.74 (–CH –(CH –CH ±, 31.06 (–CH –(CH –CH ±, 31.96 (–CH
–CH ±, 32.14 (–CH –(CH –CH
3
2
2
±
9
3
2
2
±
9
–CH
3
±, 27.95 (–CH
–(CH –CH
2
–
3
±,
2
–
(CH
2
±
9
3
2
2
±
9
3
2
2 9
±
10. Bibal, B.; Tinant, B.; Declercq, J.-P.; Dutasta, J.-P. Supramol. Chem. 2003,
2
2
2
±
9
3
2
2
±
9
3
15, 25.
(
CH
2
±
9
3
2
2
±
9
3
±, 34.21, 36.07, 117.26,
11. (a± Delangle, P.; Mulatier, J.-C.; Tinant, B.; Declercq, J.-P.; Dutasta, J.-P. Eur. J.
Org. Chem. 2001, 3695; (b± Yebeutchou, R. M.; Dalcanale, E. J. Am. Chem. Soc.
1
1
1
17.75, 118.73, 122.02, 122.51, 123.20, 127.82, 128.52, 129.28,
31.59 (d, J = 16.1 Hz±, 133.27 (d, 3J = 16.1 Hz±, 134.39, 134.81,
35.78, 136.41, 140.12, 145.92, 146.10, 152.28, 152.84.
2009, 131, 2452.
3
12. Dalla Cort, A.; Mandolini, L.; Pasquini, C.; Schiaffino, L. New J. Chem. 2004, 28,
1198.
13. Timmerman, P.; Verboom, W.; Reinhoudt, D. N. Tetrahedron 1996, 52, 2663.
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Dutasta, J.-P. J. Org. Chem. 2009, 74, 3923.
4
.7.2. Cavitand (±)-4
LSIMS m/z 1475.8478 [M+H] (calcd 1475.8491±. 31P NMR
+
1
16. Bibal, B.; Tinant, B.; Declercq, J.-P.; Dutasta, J.-P. Chem. Commun. 2002, 432.
7. Cantadori, B.; Betti, P.; Boccini, F.; Massera, C.; Dalcanale, E. Supramol. Chem.
008, 20, 29.
18. Herriott, A. W. J. Am. Chem. Soc. 1971, 93, 3304.
(
CDCl
3
, 300 K, 202.45 MHz± : d 9.01 (1P±, 9.21 (1P±. H NMR (CDCl
3
,
1
3
7
00 K, 500.10 MHz± d 0.86 (m, 12H, –CH
2H, –CH –(CH –CH ±, 2.12 (m, 2H, (–CH
–(CH –CH ±, 4.24 (m, 1H±, 4.58 (m, 1H±, 4.70 (m,
H±, 5.68 (m, 1H±, 6.40 (s, 1H±, 6.93 (s, 1H±, 7.05 (s, 1H±, 7.11 (s,
H±, 7.23 (m, 3H±, 7.26 (s, 1H±, 7.32 (s, 1H±, 7.38 (m, 1H±, 7.47
2
–(CH
2
9 3
± –CH ±, 1.25 (m,
2
2
2
±
9
3
2
2
–(CH ±
9
–CH
3
±, 2.28
1
2
2
9. Tebby, J. C. Handbook of phosphorous-31 Nuclear Magnetic Resonance Data; CRC
(
m, 4H, –CH
2
2
±
9
3
Press: Boca Raton, 1991.
0. (a± Moran, J. R.; Karbach, S.; Cram, D. J. J. Am. Chem. Soc. 1982, 104, 5826; (b±
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7748; (b± Azov, V. A.; Schlegel, A.; Diederich, F. Angew. Chem., Int. Ed. 2005, 44,
1
1
(
m, 2H±, 7.55 (m, 3H±, 7.60 (s, 1H±, 7.74 (m, 2H±, 7.90 (m, 2H±,
1
3
8
.01 (m, 2H±. C NMR (CDCl
–CH ±, 22.78 (–CH –(CH
±, 29.51 (m, –CH –(CH –CH
–(CH –CH ±, 31.23 (–CH
–CH ±, 32.12 (–CH –(CH
±, 33.92, 34.04, 35.92, 36.25, 110.29, 111.35, 117.25,
3
, 300 K, 50.32 MHz± d 14.21 (–CH
–CH ±, 28.10 (m, –CH –(CH
±, 29.80 (m, –CH –(CH –CH
–(CH –CH
–CH ±, 33.65 (–CH
2
9
3
–
–
±,
4635; (c± Pagliusi, P.; Lagugné-Labarthet, F.; Shenoy, D. K.; Dalcanale, E.; Shen,
(
CH
2
±
9
3
2
2
±
9
3
2
2
±
Y. R. J. Am. Chem. Soc. 2006, 128, 12610.
CH
3
–
3
2
±
2 9
3
2
2
±
9
22. Moran, J. R.; Ericson, J. L.; Dalcanale, E.; Bryant, J. A.; Knobler, C. B.; Cram, D. J. J.
Am. Chem. Soc. 1991, 113, 5707.
0.84 (–CH
CH –(CH
–CH
2
2
±
9
3
2
2
±
9
3
±, 32.02 (m,
2
2
3. Azov, V. A.; Diederich, F.; Lill, Y.; Hecht, B. Helv. Chim. Acta 2003, 86, 2149.
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2
2
±
9
3
2
2
±
9
3
2
–
(
CH
2
±
9
3
1
25. First example of CD spectra of a chiral resorcinarene: Mann, E.; Rebek, J., Jr.
1
17.35, 121.98, 122.34, 122.44, 123.58, 125.15 (d, J = 206.2 Hz±,
Tetrahedron 2008, 64, 8484.
1
1
25.60 (d, J = 206.2 Hz±, 128.07, 128.20, 128.37, 128.52 (d,
2
6. (a± Nafie, L. A.; Keiderling, T. A.; Stephens, P. J. J. Am. Chem. Soc. 1976, 98, 2715;
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Chirality 2003, 15, 743; (e± Gatineau, D.; Moraleda, D.; Naubron, J.-V.; Bürgi, T.;
Giordano, L.; Buono, G. Tetrahedron: Asymmetry 2009, 20, 1912; (f± Piron, F.;
Vanthuyne, N.; Joulin, B.; Naubron, J.-V.; Cisma, C.; Terec, A.; Varga, R. A.;
Roussel, C.; Roncali, J.; Grosu, I. J. Org. Chem. 2009, 74, 9062; (g± Brotin, T.;
Cavagnat, D.; Dutasta, J.-P.; Buffeteau, T. J. Am. Chem. Soc. 2006, 128, 5533; (h±
Brotin, T.; Cavagnat, D.; Buffeteau, T. J. Phys. Chem. A 2008, 112, 8464; (i±
Cavagnat, D.; Buffeteau, T.; Brotin, T. J. Org. Chem. 2008, 73, 66.
3
3
J = 16.1 Hz±, 128.56 (d, J = 16.1 Hz±, 129.27, 129.45, 129.53,
29.62, 131.15 (d, 2J = 10.1 Hz±, 131.44 (d, 2J = 10.1 Hz±, 133.23,
1
1
1
33.32, 134.30, 134.85, 135.94, 137.52, 145.39, 145.75, 145.97,
52.29, 152.44, 152.61, 152.85, 156.09.
Acknowledgments
2
7. (a± Givelet, C.; Buffeteau, T.; Arnaud-Neu, F.; Hubscher-Bruder, V.; Bibal, B. J.
Org. Chem. 2009, 74, 5059; (b± Escuder, B.; Rowan, A. E.; Feiters, M. C.; Nolte, R.
J. M. Tetrahedron 2004, 60, 291; (c± Molt, O.; Schrader, T. Angew. Chem., Int. Ed.
2003, 40, 3148; (d± Molt, O.; Rübeling, D.; Schäfer, G.; Schrader, T. Chem. Eur. J.
2004, 10, 4225.
We thank Dr. Denis Bouchu for mass spectroscopy measure-
ments (Centre de spectrométrie de masse, Université de Lyon±,
Sandrine Denis-Quanquin for NMR assistance and Professor Jérôme
Lacour and Stéphane Grass (University of Geneva± for the CD spec-
troscopy assistance. This work was supported by the computing
facilities of the Centre Régional de Compétences en Modélisation
Moléculaire de Marseille (CRCMM±.
2
8. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Rob, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G.
A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe,
M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
GAUSSIAN 03 Rev. E01 Gaussian, Inc.: Wallingford, CT, 2003.
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